William A Dunn, PhD

Eukaryotic cells adapt to environmental changes by altering their protein complements through synthesis and degradation. Cells that adapt poorly or improperly may either cease to exist (e.g., apoptosis) or become neoplastic (e.g., hepatoma). Cells adapt to low levels of amino acids by sequestering proteins and organelles for lysosomal degradation via a process called autophagy. The data suggest that autophagy protects the cells from nutrient, environmental, and chemical stresses that may cause cell death. Autophagy-mediated cell protection is likely mediated by the degradation of damaged mitochondria, which otherwise would promote cell death via apoptosis. The ability of autophagy to remove and degrade damaged mitochondria also suggests that autophagy may have a beneficial role in aging. Furthermore, cancers that effectively regulate autophagy have the potential to resist chemotherapy agents and thrive. In addition, it appears that some bacteria utilize the autophagy pathway of the host cell to escape lysosomal destruction thereby replicating within the host. Finally, we have shown that autophagy may be a major pathway for the removal of protein aggregates observed in many neuropathies and in aged cells. On the other hand, autophagy can promote cell death. Our long-term goals are to characterize the molecular aspects of the regulation and mechanisms of cellular autophagy in normal and diseased tissues. We have identified by in silico docking and powerful cellular screening methods “first-in-class” compounds that either inhibit or activate the autophagy response in mammalian cells. We currently plan to utilize these unique compounds to establish autophagy as a therapeutic target for treating cancer and other diseases. We are combining our understanding of the molecular events of autophagy with novel autophagy compounds to design clinical approaches by which to turn off autophagy and suppress the survival of chemoresistant cancers and promote the degradation of intracellular pathogens or to turn on autophagy and arrest neoplastic growth, degrade protein aggregates, and remove damaged mitochondria during aging and ishemia/reperfusion.

RESEARCH PROJECTS

Molecular Characterization of Autophagy: We are utilizing a multidisciplinary approach of cell, molecular, and genetic procedures to establish the functional roles of specific cellular proteins in selective and nonselective autophagy in mammalian cells.

The Role of Autophagy in Cancer: In collaboration with Drs. Yehia Daaka (Dept. of Anatomy and Cell Biology) and Brian Law (Dept. of Pharmacology and Therapeutics), we are utilizing genetic and pharmaceutical approaches to evaluate the role of autophagy in cell survival and cell death and in tumor growth of breast, prostate, kidney, pancreas, and liver.

Interactions between Oral Pathogens and Vascular Cells: In collaboration with Dr. Ann Progulske-Fox (Dept. of Oral Biology, College of Dentistry), we are utilizing both morphologic and genetic approaches to characterize the events of bacterial invasion in vascular endothelial cells.

Role of Autophagy in Aging: In collaboration with Drs. John Aris (Dept. of Anatomy and Cell Biology), Christiaan Leeuwenburg (Dept. of Aging and Geriatric Research) and Jae-Sung Kim (Dept. of Zoology), we are investigating in a rat aging model the autophagic responses to aging in different tissues and if autophagy can suppress aging by removing damaged mitochondria.

Role of Autophagy in Organ Transplants: In collaboration with Dr. Kim (Dept. of Surgery), we are evaluating the role of autophagy in cell death during ischemia /reperfusion.

Role of Autophagy in the Removal of Protein Aggregates: In collaboration with Dr. Lucia Notterpek (Dept. of Neuroscience), we are examining avenues by which to promote the removal and degradation of PMP22 protein aggregates by autophagy in cell and animal models of hereditary peripheral neuropathies.

Role of Autophagy in Retinal Function: In collaboration with Drs. Maria Grant and Michael Boulton (University of Indiana), we are examining the role of autophagy is the circadian rhythm and homeostasis of the retina.

0000-0002-0577-3913